Selective inhibition of <scp>FAAH</scp> produces antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid‐like fatty acid amides

Fichna, Jakub; Sałaga, Maciej; Stuart, Jordyn; Saur, Dieter; Sobczak, Marcin; Zatorski, Hubert; Timmermans, Jean‐Pierre; Bradshaw, Heather B.; Ahn, Kyunghye; Storr, Martin

doi:10.1111/nmo.12272

Cited by 59 publications

(54 citation statements)

References 41 publications

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“…A recent proof-of-principle clinical trial confirmed the clinical relevance of these findings showing improvement of abdominal pain and global relief by the H1R antagonist ebastin in patients with IBS ( Gastroenterology 2013;144(Suppl 1):S-160) 112. Palmitoylethanolamide and other inhibitors of cannabinoid receptors seem efficacious in controlling pain, motor disturbances and inflammation in animal models through modulation of neuronal and non-neuronal cells, including MCs113 114 Slow release of vitamin C may be also helpful as it increases degradation of histamine and inhibits MC degranulation in doses not superior to 750 mg/day 111. Natural flavonoids (fisetin, kaempferol, quercetin, rutin, luteolin) and the active alkaloid berberine inhibit the mediator release of MCs in vitro115 and protect intestinal epithelial barrier 114.…”

Section: Targeting Mcs: Implications For Treatment Of Fgidsmentioning

confidence: 86%

The role of mast cells in functional GI disorders

Wouters

Vicario

Santos

2015

Gut

266

237

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Functional gastrointestinal disorders (FGIDs) are characterized by chronic complaints arising from disorganized brain-gut interactions leading to dysmotility and hypersensitivity. The two most prevalent FGIDs, affecting up to 16-26% of worldwide population, are functional dyspepsia and irritable bowel syndrome. Their etiopathogenic mechanisms remain unclear, however, recent observations reveal low-grade mucosal inflammation and immune activation, in association with impaired epithelial barrier function and aberrant neuronal sensitivity. These findings come to challenge the traditional view of FGIDs as pure functional disorders, and relate the origin to a tangible organic substrate. The mucosal inflammatory infiltrate is dominated by mast cells, eosinophils and intraepithelial lymphocytes in the intestine of FGIDs. It is well established that mast cell activation can generate epithelial and neuro-muscular dysfunction and promote visceral hypersensitivity and altered motility patterns in FGIDs, postoperative ileus, food allergy and inflammatory bowel disease. This review will discuss the role of mucosal mast cells in the gastrointestinal tract with a specific focus on recent advances in disease mechanisms and clinical management in irritable bowel syndrome and functional dyspepsia.

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Section: Targeting Mcs: Implications For Treatment Of Fgidsmentioning

confidence: 86%

The role of mast cells in functional GI disorders

Wouters

Vicario

Santos

2015

Gut

266

237

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“…Inhibitors of DAGL have been examined in models of constipation; they effectively normalized slowed transit in opioid-induced constipation and in congenital slow-transit constipation 90 . Conversely, inhibiting the degradation of endocannabinoids, by blocking FAAH, has antidiarrheal and anti-nociceptive effects in models of accelerated motility and in mice with oil of mustard-induced colitis, respectively 91, 92 . In these studies, increasing levels of endocannabinoids in the gut was not associated with cannabinoid-like side effects such as reduced ambulatory locomotion.…”

Section: Cannabinoids and Control Of Gi Motilitymentioning

confidence: 99%

The Role of the Endocannabinoid System in the Brain–Gut Axis

2016

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The actions of cannabis are mediated by receptors that are part of an endogenous cannabinoid system. The endocannabinoid system (ECS) consists of the naturally occurring ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic and degradative enzymes, and the cannabinoid receptors CB1 and CB2. The ECS is a widely distributed transmitter system that controls gut functions peripherally and centrally. It is an important physiologic regulator of gastrointestinal motility. Polymorphisms in the gene encoding CB1 (CNR1) have been associated with some forms of irritable bowel syndrome. The ECS is involved in the control of nausea and vomiting and visceral sensation. The homeostatic role of the ECS also extends to the control of intestinal inflammation. We review the mechanisms by which the ECS links stress and visceral pain. CB1 in sensory ganglia controls visceral sensation, and transcription of CNR1 is modified through epigenetic processes under conditions of chronic stress. These processes might link stress with abdominal pain. The ECS is also involved centrally in the manifestation of stress, and endocannabinoid signaling reduces the activity of hypothalamic–pituitary–adrenal pathways via actions in specific brain regions—notably the prefrontal cortex, amygdala, and hypothalamus. Agents that modulate the ECS are in early stages of development for treatment of gastrointestinal diseases. Increasing our understanding of the ECS will greatly advance our knowledge of interactions between the brain and gut and could lead to new treatments for gastrointestinal disorders.

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“…or i.c.v. in stress-, neostigmine-and mustard oil-induced hypermotility in the mouse (Fichna et al 2014), but not in dextran sulphate sodiuminduced colitis . Systemic (i.p.)…”

Section: Inflammationmentioning

confidence: 98%

The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review

Fowler

2015

Handbook of Experimental Pharmacology

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The endocannabinoids anandamide and 2-arachidonoylglycerol are metabolised by both hydrolytic enzymes (primarily fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL)) and oxygenating enzymes (e.g. cyclooxygenase-2, COX-2). In the present article, the in vivo data for compounds inhibiting endocannabinoid metabolism have been reviewed, focussing on inflammation and pain. Potential reasons for the failure of an FAAH inhibitor in a clinical trial in patients with osteoarthritic pain are discussed. It is concluded that there is a continued potential for compounds inhibiting endocannabinoid metabolism in terms of drug development, but that it is wise not to be unrealistic in terms of expectations of success.

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Selective inhibition of FAAH produces antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid‐like fatty acid amides

Abstract: These data expand our understanding of the ECS function and provide a novel framework for the development of future potential treatments of functional GI disorders.

Cited by 59 publications

References 41 publications

The role of mast cells in functional GI disorders

The role of mast cells in functional GI disorders

The Role of the Endocannabinoid System in the Brain–Gut Axis

The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review

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